Genetic basis for variation in plasma IL-18 levels in persons with chronic hepatitis C virus and human immunodeficiency virus-1 infections

C Vergara¹, C Thio¹, R Latanich¹, A L Cox¹, G D Kirk², S H Mehta², M Busch³, E L Murphy^{3

4}, M C Villacres⁵, M G Peters⁴, A L French⁶, E Golub², J Eron⁷, C D Lahiri⁸, S Shrestha⁹, D Gustafson¹⁰, M Young¹¹, K Anastos¹², B Aouizerat^{13

14}, A Y Kim^{15

16}, G Lauer^{15

16}, D L Thomas¹, P Duggal²

Affiliations

¹ School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
² Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA.
³ University of California, San Francisco, CA, USA.
⁴ Blood Systems Research Institute, San Francisco, CA, USA.
⁵ Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
⁶ CORE Center/Stroger Hospital of Cook County, Chicago, IL, USA.
⁷ University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁸ School of Medicine, Emory University, Atlanta, GA, USA.
⁹ The University of Alabama at Birmingham, AL, USA.
¹⁰ State University of New York-Downstate Medical Center, New York, NY, USA.
¹¹ Georgetown University Medical Center, Washington, DC, USA.
¹² Albert Einstein College of Medicine and Montefiore Medical Center, New York, NY, USA.
¹³ Bluestone Center for Clinical Research, New York University, New York, NY, USA.
¹⁴ Department of Oral and Maxillofacial Surgery, New York University, New York, NY, USA.
¹⁵ Massachusetts General Hospital, Boston, MA, USA.
¹⁶ Harvard Medical School, Boston, MA, USA.

PMID: 28300059
PMCID: PMC5408324
DOI: 10.1038/gene.2017.2

Genetic basis for variation in plasma IL-18 levels in persons with chronic hepatitis C virus and human immunodeficiency virus-1 infections

C Vergara et al. Genes Immun. 2017 Mar.

. 2017 Mar;18(2):82-87.

doi: 10.1038/gene.2017.2. Epub 2017 Mar 16.

Authors

Affiliations

¹ School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
² Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA.
³ University of California, San Francisco, CA, USA.
⁴ Blood Systems Research Institute, San Francisco, CA, USA.
⁵ Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
⁶ CORE Center/Stroger Hospital of Cook County, Chicago, IL, USA.
⁷ University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁸ School of Medicine, Emory University, Atlanta, GA, USA.
⁹ The University of Alabama at Birmingham, AL, USA.
¹⁰ State University of New York-Downstate Medical Center, New York, NY, USA.
¹¹ Georgetown University Medical Center, Washington, DC, USA.
¹² Albert Einstein College of Medicine and Montefiore Medical Center, New York, NY, USA.
¹³ Bluestone Center for Clinical Research, New York University, New York, NY, USA.
¹⁴ Department of Oral and Maxillofacial Surgery, New York University, New York, NY, USA.
¹⁵ Massachusetts General Hospital, Boston, MA, USA.
¹⁶ Harvard Medical School, Boston, MA, USA.

PMID: 28300059
PMCID: PMC5408324
DOI: 10.1038/gene.2017.2

Abstract

Inflammasomes are multi-protein complexes integrating pathogen-triggered signaling leading to the generation of pro-inflammatory cytokines including interleukin-18 (IL-18). Hepatitis C virus (HCV) and human immunodeficiency virus (HIV) infections are associated with elevated IL-18, suggesting inflammasome activation. However, there is marked person-to-person variation in the inflammasome response to HCV and HIV. We hypothesized that host genetics may explain this variation. To test this, we analyzed the associations of plasma IL-18 levels and polymorphisms in 10 genes in the inflammasome cascade. About 1538 participants with active HIV and/or HCV infection in three ancestry groups are included. Samples were genotyped using the Illumina Omni 1-quad and Omni 2.5 arrays. Linear regression analyses were performed to test the association of variants with log IL-18 including HCV and HIV infection status, and HIV RNA in each ancestry group and then meta-analyzed. Eleven highly correlated single-nucleotide polymorphisms (r²=0.98-1) in the IL-18-BCO2 region were significantly associated with log IL-18; each T allele of rs80011693 confers a decrease of 0.06 log pg ml^-1 of IL-18 after adjusting for covariates (rs80011693; rs111311302 β=-0.06, P-value=2.7 × 10^-4). In conclusion, genetic variation in IL-18 is associated with IL-18 production in response to HIV and HCV infection, and may explain variability in the inflammatory outcomes of chronic viral infections.

PubMed Disclaimer

Conflict of interest statement

Conflict of Interest: The authors declare no conflict of interest.

Figures

**Figure 1**
Log plasma IL-18 by HCV and HIV infection status in all the individuals analyzed in the study. The thick horizontal line in each box plot represent the median for each category, the whiskers extend to 1.5 times the interquartile range from the box.

**Figure 2**
Association of variants in the *IL18-BCO2* region. The variants included 14 genotyped (squares) and 177 imputed SNPs (circles) within the region from 112 Mb to 112.1 Mb on chromosome 11. The recombination in this region is plotted in the background in light blue. Pair wise LDs between rs80011693 and other variants in *IL18-BCO2* were estimated using LD data in EUR population in the 1000 Genomes project (hg19/Nov 2014). The color from blue to red represents the r² values.

See this image and copyright information in PMC

References

1. Guo H, Callaway JB, Ting JP. Inflammasomes: mechanism of action, role in disease, and therapeutics. Nat Med. 2015 Jul;21(7):677–687. - PMC - PubMed
1. Chattergoon MA, Latanich R, Quinn J, Winter ME, Buckheit RW, 3rd, Blankson JN, et al. HIV and HCV activate the inflammasome in monocytes and macrophages via endosomal Toll-like receptors without induction of type 1 interferon. PLoS Pathog. 2014 May 1;10(5):e1004082. - PMC - PubMed
1. Kanneganti TD. Central roles of NLRs and inflammasomes in viral infection. Nat Rev Immunol. 2010 Oct;10(10):688–698. - PMC - PubMed
1. Netea MG, Simon A, van de Veerdonk F, Kullberg BJ, Van der Meer JW, Joosten LA. IL-1beta processing in host defense: beyond the inflammasomes. PLoS Pathog. 2010 Feb 26;6(2):e1000661. - PMC - PubMed
1. Dinarello CA. Interleukin-1 in the pathogenesis and treatment of inflammatory diseases. Blood. 2011 Apr 7;117(14):3720–3732. - PMC - PubMed

Publication types

Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Genetic basis for variation in plasma IL-18 levels in persons with chronic hepatitis C virus and human immunodeficiency virus-1 infections

Affiliations

Genetic basis for variation in plasma IL-18 levels in persons with chronic hepatitis C virus and human immunodeficiency virus-1 infections

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical

Miscellaneous